To seek or not to seek: leptin's role in feeding as resources become scarce

University Of Chicago, Chicago IL

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Abstract

Two-thirds of Americans are overweight or obese and around the world obesity rates are rising. A hallmark of obesity is elevated plasma leptin concentrations but a resistance to leptin signaling in the brain. Leptin circulates in the blood in proportion to the amount of white adipose tissue in the body. When food is readily- available, leptin signaling inhibits feeding and promotes energy expenditure. The resistance to leptin that occurs in diet-induced obesity is thought to be evolutionarily adaptive because it enables the accumulation of energy stores when food is readily-available, which presumably promotes survival during periods scarcity. The consequences of leptin-resistance once food becomes scarce are unclear. Evidence suggests that leptin promotes energy expenditure without inhibiting feeding when animals have access to a limited amount of food. Using homecage operant boxes, I found that mice that do not secrete leptin (ob/ob mice) overeat when food is relatively easy to obtain, but are less likely to seek food when it is relatively scarce. This suggests that leptin signaling promotes food-seeking when resources are scarce. I hypothesize that leptin's interaction with midbrain dopamine neurons is important for promoting food-seeking when the cost of acquiring it is relatively high. The dopamine system plays a critical role in feeding when work is required to obtain food. It has been shown that the absence of leptin signaling in the brain reduces intracellular dopamine production. I will test: 1) whether chronic leptin replacement in ob/ob mice restores food-seeking as scarcity increases;and 2) whether restoring dopamine production in the brain using systemic l-dopa injections restores food-seeking and/or energy expenditure as scarcity increases in ob/ob mice. To establish whether the ability of leptin to promote food-seeking is dependent on its direct effects on dopamine neurons, I will test whether leptin signaling in dopamine neurons is required for food-seeking as scarcity increases. I will induce leptin-resistance in dopamine neurons by employing a tissue-specific functional knockout of leptin receptors in dopamine neurons only.